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Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review)

  • Authors:
    • Zhiwei Yuan
    • Zheng Xia
    • Liyun Ling
    • Jingzhe Xie
    • Feng Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Songjiang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201600, P.R. China
    Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 18
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    Published online on: October 29, 2025
       https://doi.org/10.3892/mmr.2025.13728
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Abstract

Mucin 2 (MUC2) is the primary structural component of the intestinal mucus layer and is essential for maintaining the integrity of the mucus barrier and influencing the development of inflammatory bowel disease (IBD). Disruption of MUC2 production or secretion compromises barrier function, increasing susceptibility to the chronic mucosal inflammation characteristic of IBD. Given their large size and complex folding requirements, immature MUC2 precursors easily accumulate in the endoplasmic reticulum (ER) and cause ER stress, leading to activation of the unfolded protein response (UPR). The UPR restores ER homeostasis by reducing protein synthesis, enhancing folding, and degrading misfolded proteins. The mammalian UPR has three known signaling branches: Pancreatic ER kinase, ER transmembrane inositol‑requiring enzymes 1α and β (IRE1α and IRE1β) and activating transcription factor 6. Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the ER. Importantly, IRE1β‑AGR2 signaling potentially serves as a superior regulatory mechanism for controlling UPR activation caused by the misfolding of MUC2 in goblet cells. The present review highlights the critical role of MUC2 dysfunction and UPR imbalance in IBD pathogenesis. Targeting the association between novel UPR signaling pathways and restoring MUC2 protein function may provide new insights into IBD research and treatment.
View Figures

Figure 1

Domain structure and biosynthesis of
MUC2. (A) Diagrammatic representation of MUC2. (B) Assembly of the
MUC2 mucin into dimeric forms in the ER, and the formation of
trimeric forms in the Golgi network. (C) Common mucin-type
O-glycosylation Core 1–4 biosynthetic pathways. Each
oligosaccharide can be extended by various glycosyltransferases and
sulfotransferases to generate various O-glycan structures. MUC2,
mucin 2; ER, endoplasmic reticulum; VWD, von Willebrand D domains;
CK, cystine-knot; GalNAc, N-acetylgalactosamine.

Figure 2

Major UPR pathways within the ER and
UPR activation controlled by AGR2-IRE1β signaling caused by
misfolded MUC2 in goblet cells. BiP senses the presence of
misfolded proteins and releases ATF6, IRE1 and PERK to enter their
active states, resulting in transcriptional programs that decrease
ER stress. Goblet cells possess a relatively effective UPR sensor,
IRE1β, whose activity is repressed by AGR2, a cell-specific
chaperone, through a mechanism analogous to the repression of IRE1α
by BiP. CHOP, CCAAT/enhancer binding protein-homologous protein, a
master regulator of ER stress-induced apoptosis plays a
pro-apoptotic role in the stress response. ER-associated
degradation pathway transports accumulated unfolded/misfolded
proteins from the ER to the cytosol for degradation by the
ubiquitin-proteasome system. RIDD degrades mRNAs localized to the
ER membrane through IRE1 RNase activity, thereby reducing the
influx of proteins into the ER lumen. UPR, unfolded protein
response; ER, endoplasmic reticulum; AGR2, anterior gradient 2;
IRE1β, ER transmembrane inositol-requiring enzyme 1β; ATF6,
activating transcription factor 6; PERK, pancreatic ER kinase;
RIDD, regulated IRE1-dependent decay.
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Copy and paste a formatted citation
Spandidos Publications style
Yuan Z, Xia Z, Ling L, Xie J and Zhang F: Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review). Mol Med Rep 33: 18, 2026.
APA
Yuan, Z., Xia, Z., Ling, L., Xie, J., & Zhang, F. (2026). Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review). Molecular Medicine Reports, 33, 18. https://doi.org/10.3892/mmr.2025.13728
MLA
Yuan, Z., Xia, Z., Ling, L., Xie, J., Zhang, F."Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review)". Molecular Medicine Reports 33.1 (2026): 18.
Chicago
Yuan, Z., Xia, Z., Ling, L., Xie, J., Zhang, F."Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review)". Molecular Medicine Reports 33, no. 1 (2026): 18. https://doi.org/10.3892/mmr.2025.13728
Copy and paste a formatted citation
x
Spandidos Publications style
Yuan Z, Xia Z, Ling L, Xie J and Zhang F: Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review). Mol Med Rep 33: 18, 2026.
APA
Yuan, Z., Xia, Z., Ling, L., Xie, J., & Zhang, F. (2026). Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review). Molecular Medicine Reports, 33, 18. https://doi.org/10.3892/mmr.2025.13728
MLA
Yuan, Z., Xia, Z., Ling, L., Xie, J., Zhang, F."Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review)". Molecular Medicine Reports 33.1 (2026): 18.
Chicago
Yuan, Z., Xia, Z., Ling, L., Xie, J., Zhang, F."Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review)". Molecular Medicine Reports 33, no. 1 (2026): 18. https://doi.org/10.3892/mmr.2025.13728
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